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By Dr. Yuhong Dong

In brief:

  • Florida is the first state to recommend against mRNA COVID-19 vaccination of children and men up to age 39, but it joins the U.K., Sweden and Denmark in some regards.
  • The Florida Department of Health conducted a self-controlled case series with a 25-week observation period, similar to an analysis done in the U.K. The Florida study found an elevated risk of cardiac death among men ages 18 to 39 in the 28 days following mRNA COVID-19 vaccination.
  • Medical literature shows myocarditis after COVID-19 vaccination can be both immediate and severe, with rates as high as 1 in 1,862, for males ages 18-24.
  • There are several hypotheses about how the spike protein can cause this cardiac damage, particularly in young male populations. A worldwide registry of cases would help shed light on risk factors.
  • Worry about post-vaccination symptoms can create a negative feedback loop. Instead, try some of these management tips:
  • To manage anxiety, try taking a deep breath in (count to 4), hold for 4 counts, and slowly exhale for 8 counts. If you have a blood pressure cuff at home, try using biofeedback to watch your blood pressure come down using the same techniques. You will regain confidence in your body’s ability to regulate stress by asking the parasympathetic nervous system to turn off the alarms set off by the sympathetic nervous system.
  • While the recent guidance from Florida is rather shocking to some in the United States, it is reassuring to see that critical thinking is alive and well. Medicine is not stagnant, nor one-size-fits-all.

Florida Surgeon General Joseph Ladapo, M.D., Ph.D., announced on Oct. 7 that the state now recommends against mRNA COVID-19 vaccination of males ages 18 to 39 years given the results of a recent study which found an 84% increase in the risk of cardiac death among young adult males within 28 days of mRNA COVID-19 vaccination.

This follows guidance issued in March 2022 recommending against mRNA COVID-19 vaccination of healthy children and adolescents younger than 18.

As such, Florida is the only U.S. state to recommend against mRNA vaccination of healthy children and adults, but it joins the U.K., Sweden and Denmark in removing the recommendation to vaccinate healthy children younger than 11 years (U.K.) or 18 years (Sweden) and even 50 years (Denmark).

Dr. Ladapo encourages Floridians “to discuss all the potential benefits and risks of receiving mRNA COVID-19 vaccines with their health care provider.”

People in Florida can opt to get their children vaccinated based on their individual risk tolerance, and this guidance does not preclude families from seeking vaccination through pharmacies and physician offices if desired.

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Why?

The Florida Department of Health conducted a self-controlled case series to evaluate the risk of all-cause death and cardiac death after vaccination. The self-controlled case series is an established method employed frequently to assess vaccine-related adverse events.

The advantage of this method is that matched controls are not necessary because each case serves as its own control. The study period includes an exposure (vaccination) and follows the case through to the outcome being assessed (death).

The study excluded patients with a known COVID-19 infection, so the findings do not directly compare the relative risk of vaccination versus disease, one of the drawbacks of this study.

However, the question the authors sought to answer is motivated by the fact that at least 67% of young adults now have infection-acquired immunity.

Compared to the pre-Omicron era when fewer people had already recovered from SARS-CoV-2 infection, the landscape of immunity is now different. Most people have immunity through either vaccination, infection or both.

This makes it hard to detect an overall benefit of vaccination in people who are already low-risk, and likely immune, against the backdrop of a vaccine-associated cardiac risk. In fact, the Florida guidance states as much:

“With a high level of global immunity to COVID-19, the benefit of vaccination is likely outweighed by this abnormally high risk of cardiac-related death among men in this age group.”

Males over 60 years of age had a 10% increased risk of cardiac-related death within 28 days of mRNA COVID-19 vaccination, and non-mRNA COVID-19 vaccines were not found to have these increased risks among any population. This study also looked at cardiac mortality among women, but the trends were not statistically significant.

A similar study was conducted in the U.K. and released as a preprint, using nearly identical methods, such as the code on the death certificate (ICD-10 I30-I52) but did not find an elevated risk of cardiac death in young people following mRNA vaccination.

The U.K. study did, however, find a risk of cardiac death among the unvaccinated in the risk period after infection. The Florida study restricted its analysis to the vaccinated.

Some other differences in study design are worth noting. First, the Florida study included all fully vaccinated (two doses for an mRNA vaccine) individuals but excluded those with booster doses, whereas the U.K. study included those who were boosted.

Second, the U.K. study included ages 12 to 29 whereas the Florida study included ages 18 to 39. Third, the comparison periods were weeks 6 to 12 post-vaccination for the U.K. study and weeks 5-25 post-vaccination for the Florida study.

Fourth, the data capture window for the U.K. study was through February 2022, whereas the Florida study closed data capture on June 1, 2022, to allow for a 25-week observation period.

Finally, the baseline and risk periods differed as well. In the U.K. study, the risk period was the 6 weeks after vaccination while in the Florida study, the risk period was the 28 days after vaccination.

The shorter risk period in the Florida study should help exclude cardiac issues related to MIS-A (the inflammatory condition which can follow a SARS-CoV-2 infection by 4-6 weeks).

It is uncertain whether the U.K. investigators made an adjustment for the high proportion of incidental infections among those admitted to the hospital. For instance, a cardiac death related to a drug overdose might be coded as a SARS-CoV-2 cardiac death when infection may not have been the underlying cause of death.

In these cases, SARS-CoV-2 is considered “incidental” to the death. For instance, on Oct. 11, 2022, the Massachusetts Department of Health COVID-19 dashboard reported that of the 856 COVID-19-positive hospitalized patients, 293 (34%) were hospitalized primarily for COVID-19 (66% were incidental).

Both studies are subject to limitations, such as missing data on deaths not registered within the follow-up period.

In addition, the U.K. vaccine program used predominantly Pfizer (58%) and adenovirus vector (Astra-Zeneca 35%) vaccines with very few Moderna (6%) administered according to the National Health Service (as of Sept. 28, 2022).

The United States, in contrast, relied heavily on mRNA (97%, including 59% Pfizer and 38% Moderna); the adenovirus-vectored vaccine (Janssen) accounted for only 3% of doses administered according to Statista (as of September 2022).

Such a dramatic difference in mRNA vaccination usage may be a factor to consider when comparing study outcomes.

Finally, the U.K. National Health Service recommended an extended dosing interval for the primary series (12 weeks), which is thought to reduce the risk of myocarditis, and did not begin offering vaccination to adolescents until September 2021, whereas the United States began recommending vaccination in May 2021, thus potentially limiting the observation period for capturing rare events in the U.K.

Taking these methodological factors into consideration, epidemiologist Dr. Tracy Beth Høeg, Ph.D., says:

“It’s important to keep in mind that, although the Florida study found an 84 percent increase in relative incidence of cardiovascular deaths in males 18–39 post mRNA vaccine, the total number of excess cases was in the single digits, so we are not talking about a large number of deaths (though of course all deaths are a tragedy, especially of young people).

“It is far from conclusive whether or not these deaths were attributable to the vaccine due to the uncertainties outlined well in the analysis.”

Høeg provides additional perspective on how this study fits with the current literature on cardiac risk following COVID-19 mRNA vaccination in a recent commentary.

Høeg has collaborated on several vaccine-associated myocarditis research projects, including serving as senior author, along with Allison Krug, M.P.H., and Josh Stevenson, on a stratified risk-benefit analysis of mRNA vaccination in adolescents ages 12-17.

Høeg explains:

“The confidence interval on the (Florida cardiac mortality) estimate was also wide and the lower end was very close to 1 so we may just be talking about a couple of deaths that created this signal. We also don’t have information on whether or not there were excess deaths after the 28 day ‘risk period’ due to the design of the study.

“The signal of increased cardiac death risk post-mRNA vaccine should be taken seriously, particularly because of what we know about the risk of post-vaccination myocarditis, but this study should only be used in the context of other studies and other lines of evidence.”

One should also note that the Florida study did not include booster doses nor adolescents younger than 18 years.

When looking at vaccine-associated myocarditis (heart inflammation) we note that excess risk is associated with the primary series in younger adolescent males, a concern that prompted Florida’s March 2022 guidance against vaccinating healthy children and adolescents younger than 18 years.

The Centers for Disease Control and Prevention (CDC) has reported 200.3 per million post-booster myocarditis risk in males ages 16 to 17 (or 1 in 5,000, Vaccine Safety Datalink, or VSD, data, slide 25), higher than ages 18-29 (47.6 to 70.3 per million, slide 34).

A potentially useful follow-on study might consider expanding the Florida age groups down to 12 years as the U.K. did and include boosters as exposures in addition to primary series doses.

Clinical evidence supports this guidance

The data thus far on cardiac outcomes following mRNA COVID-19 vaccination are compelling for myocarditis among males younger than 40 years, both with the primary series and booster.

Rates of myopericarditis after the second mRNA COVID-19 vaccination dose are 1 in 2,650 among males 12-17 and 1 in 1,862 among males ages 18-24. After the booster among males ages 18-39, the rate is 1 in 7,000.

Although media reports of myopericarditis frequently describe cases as “mild” with rapid recovery, the published literature — including from the CDC — demonstrates otherwise. A 22-year-old Korean man developed chest pain 5 days after the first dose of BNT162b2 (Pfizer) vaccination and died of autopsy-confirmed myocarditis in 7 hours.

Even among those hospitalized and then discharged, the long-term prognosis of myocarditis with respect to sudden cardiac death or all-cause mortality is not yet known. Several follow-up case series and survey studies have found concerning rates of persistent inflammation on cardiac MRI in approximately 70-80% of cases 3-8 months later.

In a recent CDC Vaccine Adverse Event Reporting System (VAERS) study published in The Lancet, 93% of myocarditis cases were hospitalized, one in four were admitted to the intensive care unit and one was put on the most invasive life-saving equipment available (extracorporeal membrane oxygenation, or ECMO).

Cardiologist Anish Koka, M.D., reviewed the CDC paper and finds the conclusions all but reassuring:

“The current study should dispel the ludicrous notion that clinical myocarditis — a disease entity that comes to light when you have chest pain because cells in your heart are dying — is mild.”

By a minimum of 90 days (median 143 days) after initial hospitalization, a third of patients were not fully recovered, 31% had activity restrictions, and 26% were still on cardiac medications (beta blockers and colchicine, predominantly).

Cardiologist Sanjay Verma, M.D., FACC (Fellow, American College of Cardiology), concurs in a recent commentary on the CDC’s findings. “It is important to note that on follow-up, 50 percent of children still had symptoms, a staggering 60 percent were lost to follow-up or were excluded from analysis, and 80 percent had no prior underlying health concerns.”

Basic research evidence and hypotheses regarding cardiac damage

Why are both disease and vaccination a risk? And why might vaccination be a particular risk in the younger population?

The spike protein gains entry to the cell via a transmembrane protein (TMPRSS2) and the ACE2 receptor, which is expressed in the airways, the gut, heart, liver, blood vessels and kidneys.

Research during the past two years has elucidated several hypotheses related to the direct and indirect impacts of the SARS-CoV-2 spike protein on the heart and microvasculature. An exaggerated immune response may also play a role in cardiac injury.

This affinity of the spike protein for ACE2 also explains why SARS-CoV-2 can have broad systemic effects if the immune system is not able to stop it in its tracks quickly.

  • Infection-related cardiac injury

Direct cardiac damage and abnormal cardiac rhythms can occur with even a mild SARS-CoV-2 infection. Two studies of heart rhythm found evidence of cell-to-cell spread via spike protein-mediated fusion (syncytia) in the heart, allowing the virus to spread surreptitiously from cell to cell.

Following the death of a young 3-month postpartum, 35-year-old Hispanic woman after a week of mild fever, evaluation of the myocardium found evidence of cardiomyocytes with SARS-CoV-2 spike glycoprotein in linearly arrayed t-tubules.

The investigators hypothesized that the woman’s sudden cardiac death was caused by immune cells carrying SARS-CoV-2 to the myocardium. Intercellular connections created by the spike glycoprotein created membrane fusions which then triggered abnormal electrophysiological activity and a fatal arrhythmia.

To further explore these arrhythmias, another study used pluripotent stem cell-derived cardiomyocytes to detect specific abnormalities related to the formation of spike-mediated syncytia.

The infected cells produced multinucleated giant cells (syncytia) with increased cellular capacitance (the ability to store an electrical charge). The syncytia also showed CA2+ handling abnormalities, including sparks and large “tsunami”-like waves.

In another self-controlled case series study among the U.K. population, Pantone, et al., found an increased risk of arrhythmias following SARS-CoV-2 infection, particularly among people ages 40 and older. This study also evaluated the risk of arrhythmias following vaccination, stratified by age <40 years or 40+ years.

In short, the relative risks of cardiac rhythm abnormalities associated with infection increased with age, while those for vaccination decreased with age (supplementary table 3a).

The spike protein may also affect the microvasculature by causing disruptions to the pericytes (cells involved in contracting blood vessels). In an in vitro study, exposure to the spike protein caused signaling and functional alterations which suggest that the spike protein may prompt pericyte dysfunction and contribute to microvascular injury.

Infection can also cause indirect cardiac injury through an exaggerated cytokine response resulting in an autoimmune attack on the heart. In a laboratory study that treated cardiomyocytes (heart muscle cells) with spike protein, the cardiomyocytes did not demonstrate increased apoptosis (cell death).

Instead, the investigators found “significantly suppressed viability” when the cardiomyocytes were exposed to peripheral blood mononuclear cells (lymphocytes, including T cells, B cells and natural killer cells) pre-conditioned with exposure to spike protein.

In other words — they tried seeing if the cardiomyocytes died upon exposure to spike protein directly, or if they died following exposure to cytokines primed by contact with the spike protein. The investigators concluded that SARS-CoV-2 infection may cause heart injury indirectly through over-activated cytokines.

  • Vaccination-associated cardiac injury

Other research to elucidate the pathway by which mRNA COVID-19 vaccination might increase the risk of myopericarditis among young males focuses on the role of catecholamines.

While this hypothesis requires further investigation, a scoping review of the literature found concluded that:

“The epidemiological, autopsy, molecular, and physiological findings unanimously and strongly suggest a hypercatecholaminergic state is the critical trigger of the rare cases of myocarditis due to components from SARS-CoV-2, potentially increasing sudden deaths among elite male athletes.”

This elevated catecholaminergic state is potentiated by mRNA spike protein produced in the adrenal medulla chromaffin cells (responsible for catecholamine production).

This leads to enhanced noradrenaline activity which is associated with a higher resting catecholamine production in male athletes and increased sensitivity in the presence of androgens.

In other words, the increased risk of myocarditis among young males strongly suggests an androgenic (male sex hormone) link coupled with the established effects of spike protein on the cardiac myocytes.

Taken together, this intriguing hypothesis suggests that, in addition to age and sex, androgen expression and athletic activity may predispose the occurrence of myopericarditis following mRNA vaccination.

Another theory was explored in a study of antibody-mediated heart inflammation conducted by German doctors among a group of 61 patients, 40 of whom were found to have biopsy-confirmed myocarditis following SARS-CoV-2 mRNA vaccination.

Young age (<21 years) seemed to be correlated with presence of anti–IL1-RA antibodies: 9 of 12 patients (75%) under 21 had the antibodies compared with 3 of 28 patients (11%) 21 years or older.

These antibodies were not found in patients lacking evidence of myocarditis. Presence of these antibodies seemed to be associated with early onset of symptoms, generally after dose two of an mRNA COVID-19 vaccine, and a milder course of myocarditis compared to those who were lacking the antibodies.

  • Why might age be a factor?

Systemic adverse events (reactogenicity) following vaccination include fever, muscle aches, headache and other systemic effects that disrupt daily activities. Due to the waning vigor of the immune system with age (called immune senescence), reactogenicity has been found to be higher among younger adults (<50 years).

Mixing products from different manufacturers (heterologous dosing) also increases reactogenicity, ostensibly because the difference in antigens between manufacturers stimulates the immune system.

Systemic adverse events also appear to be twice as likely if the person had SARS-CoV-2 previously because the ancestral vaccine antigen is not only different than the most recent viral exposure, the vaccine is serving as a booster on top of immunity derived from infection.

Another study conducted among healthcare workers found that prior SARS-CoV-2 infection tripled the risk of a systemic reaction disrupting work or daily activities after the first dose. These considerations underscore the importance of carefully weighing risks and benefits of vaccination according to age, history of infection and underlying health status.

Although the precise mechanism of cardiac injury following infection and vaccination is not fully understood, the following trends are generally supported by the literature:

  1. Cardiac damage following infection tends to increase with age.
  2. Cardiac damage following vaccination tends to be higher among those younger than 40 years, and males in particular.
  3. Younger age increases the likelihood of systemic adverse effects disrupting work and daily activities.

Other contributory factors to sudden death

Several other lines of research are exploring factors that may contribute to sudden death, such as foreign materials and fibrous clot formation following vaccination. The pandemic has contributed to global cooperation in health research at an unprecedented level, opening doors to collaboration on research related to vaccine safety as well.

To this end, an important contribution to understanding the etiology of myopericarditis and cardiac mortality would be to establish a registry of cases worldwide. Such a registry would facilitate research regarding potential risk factors beyond age and sex.

For instance, if androgens are important to catecholamine expression, what role might T-boosting (testosterone replacement therapy) among young male athletes and bodybuilders play in vaccine-associated myopericarditis or sudden cardiac death?

Does exertion exacerbate cardiac injury and arrhythmias? What about genetic markers, such as HLA haplotype?

Suggestions for those struggling with anxiety

Those who were anxious about vaccination may be particularly worried about post-vaccination side effects. This can create an unfortunate negative feedback loop, inducing more stress, anxiety and even a panic attack.

The symptoms associated with panic — chest pain, tightness, shortness of breath, and heart palpitations — can be difficult for a patient to tease apart from cardiac concerns.

The following general advice about managing anxiety in no way serves as medical guidance following mRNA COVID-19 vaccination adverse events. It is important to seek care immediately if you have any adverse reactions following vaccination of any kind.

To manage anxiety, try drawing a deep breath in (count to 4 while inhaling), hold your breath for 4 counts, and slowly exhale for 8 counts. If you have a blood pressure cuff at home, try using this method to bring your blood pressure down.

You will regain confidence in your body’s ability to regulate stress by asking the parasympathetic nervous system to turn off the alarms set off by the sympathetic nervous system.

Muscle aches, headache and other complaints (such as fever) can be treated with over-the-counter pain relief.

These symptoms affect at least 1 in 3 people who receive an mRNA COVID-19 vaccine, and are more common among those younger than 50 years, those who received different brands (heterologous dosing), or have previously been infected with SARS-CoV-2 (most of us at this point).

Get enough rest, eat well, avoid caffeine and do something enjoyable and distracting (humor is important!).

Remember that your own brain can produce some of the most powerful neurotransmitters on the planet. Getting together with loved ones or friends and having a good laugh releases oxytocin. Eating dinner with a glass of wine releases dopamine (so does exercise or doing something challenging that requires focus).

If playing a strategy game helps you unwind, do that. Listen to a podcast, or perhaps if you are learning a second language, try listening to a podcast in your target language. Simple activities like mowing the lawn, weeding, walking the dog, doing a crossword puzzle or playing Wordle can be meditative, too.

Perspective

The value of mRNA COVID-19 vaccination is in reducing death among those at highest risk, especially those with immunocompromising conditions or the most elderly.

Strategic boosting of those at highest risk is the way forward, according to Paul Offit, M.D., director of the Vaccine Education Center and professor of pediatrics in the Division of Infectious Diseases at Children’s Hospital of Philadelphia.

In a recent discussion on This Week in Virology he advocates focusing on the elderly, those living in long-term care facilities and those with immunocompromising conditions.

A study conducted in Sweden supports this approach: a booster dose provided 40% to 70% reductions in all-cause mortality among the most frail during the Omicron wave.

While the recent guidance from Florida is rather shocking to some in the United States, it is reassuring to see that critical thinking is alive and well in policy formation. It is uncomfortable to reconsider past policy in the light of new evidence, but this is what medicine is all about — it is not a stagnant, formulaic practice.

The pandemic has taught us that rigid, binary thinking and one-size-fits-all policy sometimes cause unintended harms.

It is time to move past a rigid, narrow focus on eliminating COVID-19, conduct properly powered clinical trials, make person-level trial data available for independent research on adverse events and open risk-benefit analyses to public scrutiny before public health policy decisions are made.

  • Not all high-tech is wise to deploy.
  • Not all viruses need a vaccine.
  • Not all vaccines are good or protective.
  • Not everyone needs a vaccine.

References

Cardiac death studies:

Clinical evidence:

Basic research evidence:

Reprinted with permission from The Epoch Times.

Dr. Yuhong Dong, a medical doctor who also holds a doctorate in infectious diseases, is the chief scientific officer and co-founder of a Swiss biotech company and former senior medical scientific expert for antiviral drug development at Novartis Pharma in Switzerland.